EP1023062B1 - Carbapenemes antibacteriens, compositions et methodes de traitement - Google Patents

Carbapenemes antibacteriens, compositions et methodes de traitement Download PDF

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EP1023062B1
EP1023062B1 EP98953450A EP98953450A EP1023062B1 EP 1023062 B1 EP1023062 B1 EP 1023062B1 EP 98953450 A EP98953450 A EP 98953450A EP 98953450 A EP98953450 A EP 98953450A EP 1023062 B1 EP1023062 B1 EP 1023062B1
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alkyl
compound
accordance
groups
substituted
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EP1023062A4 (fr
EP1023062A1 (fr
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Timothy A. Blizzard
Ronald W. Ratcliffe
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Merck and Co Inc
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/14—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to carbapenem antibacterial agents in which the carbapenem nucleus is substituted at the 2-position with a naphthosultam linked through a CR 2 R 3 group.
  • the naphthosultam is further substituted with various substituent groups including at least one cationic group -L-Q-R q .
  • the carbapenems of the present invention are useful against gram positive microorganisms, especially methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS).
  • MRSA methicillin resistant Staphylococcus aureus
  • MRSE methicillin resistant Staphylococcus epidermidis
  • MRCNS methicillin resistant coagulase negative Staphylococci
  • Carboxylate anion refers to a negatively charged group -COO - .
  • alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight or branched. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. When substituted, alkyl groups may be substituted with up to 3 substituent groups, selected from R b , R c , R e and R q as defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group”.
  • Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused.
  • Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. When substituted, cycloalkyl groups may be substituted with up to 3 substituents selected from R c , R c , R q and R e .
  • a C1-4 alkylene group refers to an alkyl group which is attached threough two bonds to two different atoms or substituents.
  • the two bonds on the alkylene group can be on the same carbon atom or on different carbon atoms. See, e.g., the following:
  • alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond.
  • Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
  • alkynyl refers to a hydrocarbon radical straight or branched, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond.
  • Preferred alkynyl groups include ethynyl, propynyl and butynyl.
  • Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like.
  • An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms.
  • the preferred aryl groups are phenyl, naphthyl and phenanthrenyl.
  • Aryl groups may likewise be substituted as defined.
  • Preferred substituted aryls include phenyl and naphthyl.
  • heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of this type are pyrrole, pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole. Examples include the following:
  • the group L-Q-R q is attached to either of the two phenyl rings of the naphthosultam group, provided that no more than one L-Q-R q group is present.
  • Heteroarylium refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge. Examples include the following:
  • heterocycloalkyl refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by hetero atoms.
  • quaternary nitrogen and “positive charge” refer to tetravalent, positively charged nitrogen atoms including, e.g., the positively charged nitrogen in a tetraalkylammonium group (e. g. tetramethylammonium), heteroarylium, (e.g., N-methyl-pyridinium), basic nitrogens which are protonated at physiological pH, and the like.
  • Cationic groups thus encompass positively charged nitrogen-containing groups, as well as basic nitrogens which are protonated at physiologic pH.
  • heteroatom means O, S or N, selected on an independent basis.
  • Halogen and "halo" refer to bromine, chlorine, fluorine and iodine.
  • protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene, T. W. et al. Protective Groups in Organic Synthesis Wiley, New York (1991). Examples of suitable protecting groups are contained throughout the specification.
  • M is a readily removable carboxyl protecting group
  • P represents a hydroxyl which is protected by a hydroxyl-protecting group.
  • Such conventional protecting groups consist of groups which are used to protectively block the hydroxyl or carboxyl group during the synthesis procedures described herein.
  • These conventional blocking groups are readily removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule.
  • Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with a transition metal catalyst and a nucleophile and catalytic hydrogenation.
  • carboxyl protecting groups include allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl such as t-butyldimethylsilyl (TBDMS), phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, p-nitrobenzyl, 4-pyridylmethyl and t-butyl.
  • C-6 hydroxyethyl protecting groups examples include triethylsilyl, t-butyldimethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and the like.
  • the carbapenem compounds of the present invention are useful per se and in their pharmaceutically acceptable salt and ester forms for the treatment of bacterial infections in animal and human subjects.
  • pharmaceutically acceptable ester, salt or hydrate refers to those salts, esters and hydrated forms of the compounds of the present invention which would be apparent to the pharmaceutical chemist. i.e., those which are substantially non-toxic and which may favorably affect the pharmacokinetic properties of said compounds, such as palatability, absorption, distribution, metabolism and excretion.
  • Other factors, more practical in nature, which are also important in the selection are cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.
  • pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
  • the present invention is also concerned with pharmaceutical compositions and methods of treating bacterial infections utilizing as an active ingredient the novel carbapenem compounds.
  • -CO 2 M which is attached to the carbapenem nucleus at position 3, this represents a carboxylic acid group (M represents H), a carboxylate anion (M represents a negative charge), a pharmaceutically acceptable ester (M represents an ester forming group) or a carboxylic acid protected by a protecting group (M represents a carboxyl protecting group).
  • the pharmaceutically acceptable salts referred to above may take the form -COOM, where M is a negative charge, which is balanced by a counterion, e.g., an alkali metal cation such as sodium or potassium.
  • Counterions may be calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.
  • the pharmaceutically acceptable salts referred to above also include acid addition salts.
  • the Formula I compounds can be used in the form of salts derived from inorganic or organic acids. Included among such salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate
  • Acid addition salts of the compounds of formula I include compounds that contain a protonated, basic moiety in R q or R.
  • Compounds containing a basic moiety in R q or R are capable of protonation in aqueous media near pH 7, so that the basic moiety can exist as an equilibrium mixture of its neutral form and acid addition (protonated) form.
  • the more basic the group the greater the degree of protonation near pH 7.
  • -NR f R g would likely be present in its protonated form, -N + HR f R g X - at the appropriate pH, where X - is a charge balancing group. All such compounds are included in the present invention.
  • all compounds which have one or more cations are balanced with one or more, as necessary, of a charge balancing group X - or Y - .
  • all compounds having one or more anions are counter balanced with one or more, as necessary, charge balancing counterion.
  • the pharmaceutically acceptable esters are such as would be readily apparent to a medicinal chemist, and include, for example, those described in detail in U.S. Pat. No. 4,309,438. Included within such pharmaceutically acceptable esters are those which are hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and others described in detail in U.S. Pat. No. 4,479,947. These are also referred to as "biolabile esters".
  • Biolabile esters are biologically hydrolizable, and may be suitable for oral administration, due to good absorption through the stomach or intenstinal mucosa, resistance to gastric acid degradation and other factors.
  • biolabile esters include compounds in which M represents an alkoxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl group.
  • M species are examples of biolabile ester forming moieties.: acetoxymethyl, 1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1-isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl, phthalidyl and (2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl.
  • X - and Y - can be present or absent as necessary to maintain the appropriate charge balance. When present, these represent pharmaceutically acceptable counterions. Most anions derived from inorganic or organic acids are suitable. Representative examples of such counterions are the following: acetate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, benzoate, benzenesulfonate, bromide, citrate, camphorate, camphorsulfonate, chloride, estolate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate, lactobionate, malate, maleate, mandelate, methanesulfonate, pantothenate, pectinate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate and tosylate. Other suitable anionic species will be apparent
  • the counterion indicator may represent a specie with more than one negative charge, such as malonate, tartrate or ethylenediaminetetraacetate (EDTA), or two or more monovalent anions, such as chloride, etc.
  • EDTA ethylenediaminetetraacetate
  • an appropriate number of carbapenem molecules can be found in association therewith to maintain the overall charge balance and neutrality.
  • L is a C 1-4 straight or branched alkylene group that is interrupted or terminated by 1-2 of O, S, NR a .
  • C(O), CO 2 and C(O)NR a the interrupting/terminating moiety or moieties can be at either end of the alkylene group, as well as interrupting the alkylene group when 2-4 carbon atoms are present.
  • 2 such groups may be separate or together.
  • interrupting or terminating groups such as OC(O) and OCO 2 are included.
  • R q When an R q is substituted with at least 2 R c groups, these may be taken in combination with any intervening atoms to represent a 3-6 membered carbocyclic ring, said ring being optionally interrupted by 1-3 of O, S, NR g and C(O), and unsubstituted or substituted with 1-3 R e groups.
  • groups which are represented by two R c groups in combination include the following:
  • R 2 and R 3 such as when R 2 represents H and the R 3 represents C 1-3 alkyl, the compounds may exist in R and S stereoisomeric forms at the CR 2 R 3 stereocenter. Both isomers are included in the present invention, in pure form as well as in mixture.
  • a subset of compounds of formula I which is of interest relates to those compounds where R 1 represents methyl. Within this subset, all other variables are as originally defined.
  • M represents a carboxylate anion.
  • M in this instance represents a negative charge which is balanced by a positively charged group, such as in the positively charged Q group.
  • a negatively charged counterion may be present which in combination with the carboxylate anion, provides overall charge neutrality.
  • Another subset of compounds of formula I that is of interest relates to those compounds where P represents hydroxyl or hydroxyl protected by a hydroxyl protecting group. Within this subset, all other variables are as originally defined.
  • R 2 represents H and R 3 is C 1-3 alkyl.
  • R 2 represents H and R 3 represents CH 3 (Me) or ethyl (Et).
  • all other variables are as originally defined.
  • R 2 and R 3 are taken in combination, and represent C 1-3 alkylidene.
  • all other variables are as originally defined.
  • Another subset of compounds of formula I that is of interest relates to compounds where L represents -CH 2 - or -CH 2 CH 2 -. Within this subset, all other variables are as originally defined.
  • Another subset of compounds of formula I that is of interest relates to compounds where Q represents wherein Y - represents a charge balancing group. Within this subset, all other variables are as originally defined.
  • R 2 is H and R 3 is CH 3 or CH 2 CH 3 .
  • the TES protected hydroxyl group in (C) or, preferably, its cyclized carbapenem product can be deprotected using an acid, such as triflic acid, or a fluoride source, such as Bu 4 NF.
  • the alcohol group of (D) can be activated towards replacement by the nucleophile Q'-R q ', in any of a number of ways. For example, when L is CH 2 , the hydroxyl group can be converted to a sulfonate derivative, such as methanesulfonyloxy, and then to an iodide derivative.
  • the hydroxy group can be converted to a trifluoromethanesulfonyloxy (triflate) derivative by reaction with triflic anhydride.
  • the activated intermediate can be combined with the reagent Q'-R q ' in an inert solvent or neat to provide the displacement product (E). This may involve a neutral moiety which becomes mono-quaternary upon reaction or a mono-quaternary moiety which becomes bis-quaternary upon reaction.
  • monocylic B-lactam (A') which contains an activated carboxylic acid derivative can be reacted with a metallated trimethylsilylalkane (F) to afford the silylalkyl ketone (G).
  • F metallated trimethylsilylalkane
  • G silylalkyl ketone
  • Intermediates of type (F) are well known and easily prepared. Bromination of (G) affords the bromoalkyl ketone (H) which can be reacted with a naphthosultam (J) in the presence of a base, such as NaHCO 3 or NaH, to afford the intermediate (K).
  • the azetidinone (K) can be converted to the ylide (C) using the standard, three-step process involving sequential reactions with a glyoxylic acid ester, a chlorinating agent such as SOCl 2 , and triphenylphosphine.
  • the B-lactam ylide (C) can be processed as described above (See Flow Chart I) to afford final products Ia.
  • the naphthosultamyl vinyl stannane (M) which is used in the cross coupling reaction to produce the carbapenem intermediate (N) can be prepared by the methods described in Flow Chart IV.
  • the naphthosultam precursor to the organometallic species (B) employed in Flow Chart I can be prepared by the methods outlined in Flow Chart V.
  • the reactions shown in Flow Charts IV and V are analogous to reactions previously described for the N-functionalization of carbamate and imide substrates.
  • Triethylamine (691 mL, 4.96 mol) was added to an ice cold solution of 1-(2-hydroxy-ethyl)-naphthalene (569 g, 3.30 mol) in dichloromethane (2.2 L). Acetyl chloride (282 mL, 3.97 mol) was added dropwise over 90 minutes. After the addition was complete, the reaction mixture was stirred for an additional 30 minutes with ice-bath cooling.
  • reaction mixture was washed sequentially with water (2 x 1 L), 1N HCl (1 L, 500 mL), water (1 L), 5% aqueous NaHCO 3 (500 mL), water (1 L), and brine (500 mL), then dried over magnesium sulfate, filtered, and evaporated to afford 1-(2-acetoxy-ethyl)-naphthalene (723.2 g) as a yellow oil that slowly crystallized.
  • the solid was collected by filtration, washed with cold water (100 mL), then dried under vacuum at 60 °C to afford a second crop of potassium 4-(2-acetoxy-ethyl)-naphthalene-1-sulfonate (10.67 g) as a white solid.
  • the second crop contained ca. 14% of the isomeric potassium 5-(2-acetoxy-ethyl)-1-naphthalene sulfonate as determined by 1H NMR.
  • Step 3 4-(2-Acetoxy-ethyl)-naphthalene-1-sulfonyl chloride
  • Step 4 4-(2-Acetoxy-ethyl)-8-nitro-naphthalene-1-sulfonyl chloride
  • Powdered cesium carbonate (76.8 g, 236 mmol) was added to a solution of 4-(2-hydroxy-ethyl)-8-nitro-naphthalene-1-sulfonamide (30.77 g, 94.3 mmol) in anhydrous dimethylformamide (470 mL).
  • the mixture was placed under a nitrogen atmosphere, sonicated for 10 minutes, then stirred at room temperature for 20 minutes.
  • the mixture was then placed in a 100 °C oil bath and stirred vigorously. After 3.5 hours, the reaction mixture was removed from the heating bath, allowed to cool to room temperature, and left at room temperature overnight. The mixture was then filtered and the collected solid was washed with dimethylformamide. The combined filtrate and washings were evaporated to a dark oil.
  • Step 7 4-(2-Triethylsilanyloxy-ethyl)-1,8-naphthosultam
  • Chlorotriethylsilane 13.57 mL, 80.86 mmol was added dropwise over 1 minute to a vigorously stirred suspension of 4-(2-hydroxy-ethyl)-1,8-naphthosultam (17.53 g, 70.32 mmol) and imidazole (5.99 g, 87.90 mmol) in dichloromethane (351 mL).
  • the reaction mixture was stirred under a nitrogen atmosphere at room temperature for 15 minutes, then water (350 mL) was added.
  • the organic layer was washed sequentially with 0.2 N HCl (350 mL) and water (350 mL) then dried over magnesium sulfate, filtered, and evaporated under vacuum to a dark oil (29.07 g).
  • the crude product was purified by flash column chromatography on silica gel (5 x 27 cm column, eluted with 4:1 hexanes-EtOAc followed by 3:1 hexanes-EtOAc) to afford a deep red oil (23.9 g).
  • the oil was mixed with hexanes (225 mL), sonicated to start crystallization, and stirred at room temperature.
  • reaction mixture was washed with water (300 mL), 1N hydrochloric acid (200 mL) and water (250 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum to afford the title compound as an oil (55.1 g).
  • Step 3 Potassium 3-(2-acetoxy-ethyl)-4-bromo-naphthalene-1-sulfonate
  • the aqueous phase was washed with methylene chloride (150 mL), briefly pumped under vacuum, then brought to pH 8 with 3M aqueous potassium hydroxide (30 mL) followed by 4M aqueous potassium carbonate (35 mL). The resulting mixture was stirred in a cold room (5°C) for 2 hours and filtered to remove the product. The recovered white solid was vacuum dried to afford the title compound (11.21 g).
  • Step 4 3-(2-Acetoxy-ethyl)-4-bromo-naphthalene-1-sulfonyl chloride
  • Step 5 3-(2-Acetoxy-ethyl)-4-bromo-8-nitro-naphthalene-1-sulfonyl chloride
  • the oganic solution was washed with water (100 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and left to stand at room temperature.
  • the organic solution deposited a solid which was collected by filtration, washed with ethyl acetate (2 x 15 mL), and vacuum dried to give the title comound (1.78 g). Additional poduct (1.88g) was obtained from the mother liquors after concentration under vacuum and crystallization from diethyl ether.
  • Step 10 3-(2-Triethylsilanyloxy-ethyl)-1,8-naphthosultam
  • Step 1 N-(2-Bromo-ethyl)-4-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultam
  • Potassium tert-butoxide (3.70 g, 33 mmol) is added to a solution of 4-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultam (10.91 g, 30 mmol) in anhydrous dimethyl sulfoxide (30 mL).
  • the reaction mixture is placed under a nitrogen atmosphere and stirred at room temperature for 10 minutes, then treated with 1,2-dibromo-ethane (3.1 mL, 36 mmol).
  • the resulting mixture is stirred at room temperature for 5 minutes then heated in an oil bath at 50°C for 21 hours.
  • the mixture is diluted with ethyl acetate (400 mL) and washed with water (200 mL), 0.1M hydrochloric acid (200 mL), 5% aqueous sodium bicarbonate (200 mL) and brine (200 mL).
  • the organic phase is dried over magnesium sulfate, filtered and evaporated under vacuum. The residue is triturated with hexanes to afford the title compound.
  • Step 2 4-(2-Triethylsilanyloxy-ethyl)-N-vinyl-1,8-naphthosultam
  • the mixture is diluted with ethyl acetate (200 mL), washed with water (4 x 150 mL) and brine (150 mL), dried over magnesium sulfate, filtered and evaporated under vacuum. The residue is purified by flash chromatography on silica gel to provide the title compound.
  • Step 3 N-(1,2-Dibromo-ethyl)-4-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultam
  • Step 4 N-(1-Bromo-vinyl)-4-(2-triethylsilanyloxy-methyl)-1,8-naphthosultam
  • reaction mixture is diluted with dichloromethane (200 mL), washed with water (100 mL) and brine (100 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum. The residue is purified by silica gel chromatography to afford the title compound.
  • Step 5 N-(1-Tributylstannanyl-vinyl)-4-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultam
  • the mixture is allowed to gradually warm to 0°C over 45 minutes and then diluted with ethyl acetate (100 mL), washed with water 100 mL) and brine (50 mL), dried over magnesium sulfate, filtered and evaporated under vacuum.
  • the crude product is purified by flash chromatography on silica gel to provide the title compound.
  • Step 1 4-Nitrobenzyl (1S,5R,6S)-1-methyl-6-[(1R)-triethylsilanyloxy-ethyl]-2-[1-[4-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultamyl]-vinyl]-carbapen-2-em-3-carboxylate
  • reaction mixture is diluted with ethyl acetate (50 mL), washed with water (3 x 30 mL) and brine (30 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum. The residue is purified by flash chromatography on EM silica gel 60 to provide the title compound.
  • Step 2 4-Nitrobenzyl (1S,5R,6S)-2- ⁇ 1-[4-(2-hydroxy-ethyl)-1,8-naphthosultamyl]-vinyl ⁇ -1-methyl-6-[(1R)-triethylsilanyloxy-ethyl]-carbapen-2-em-3-carboxylate
  • Tetrabutylammonium fluoride (1.0 ml of a 1.0M solution in tetrahydrofuran, 1 mmol) is added to an ice-cold solution of 4-nitrobenzyl (1S,5R,6S)-1-methyl-6-[(1R)-triethylsilanyloxy-ethyl]-2- ⁇ 1-[4-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultamyl]-vinyl ⁇ -carbapen-2-em-3-carboxylate (848 mg, 1.0 mmol) and acetic acid (0.085 mL, 1.5 mmol) in anhydrous tetrahydrofuran (4 mL).
  • Step 3 4-Nitrobenzyl (1S,5R,6S)-1-methyl-6-[(1R)-triethylsilanyloxy-ethyl]-2- ⁇ 1-[4-(2-trifluoromethanesulfonyloxy-ethvl)-1,8-naphthosultamyl]-vinyl ⁇ -carbapen-2-em-3-carboxylate
  • Step 4 4-Nitrobenzyl (1S,5R,6S)-2-(1- ⁇ 4-[2-(4-carbamoylmethyl-1,4-diazonia-bicyclo[2.2.2]oct-1-yl)-ethyl]-1,8-naphthosultamyl ⁇ -vinyl)-1-methyl-6-[(1R)-triethylsilanyloxy-ethyl]-carbapen-2-em-3-carboxylate bis(trifluoro-methanesulfonate)
  • the reaction mixture is added to a mixture of butanol (1.3 mL), ethyl acetate (0.65 mL), 1M pH 7 phosphate buffer (0.65 mL), and water (1.3 mL).
  • 5% Rhodium on carbon (15 mg) is added and the resulting mixture is sirred vigorously under a hydrogen atmosphere at room temperature.
  • the reaction mixture is filtered through a prewashed (tetrahydrofuran/water) bed of celite.
  • the organic portion of the filtrate is separated and extracted with water (3 x 1 mL).
  • the extracts are used to wash the filter cake and then combined with the original aqueous layer.
  • the aqueous solution is washed with 1:1 ethyl acetate-diethyl ether (2 x 5 mL) then concentrated under vacuum to approximately 4 mL volume.
  • the aqueous solution is loaded onto a column of Bio-Rad Macro Prep weak cation-exchange resin (4 mL).
  • the column is eluted with water (20 mL ) followed by 5% aqueous sodium chloride (8 x 2 mL fractions).
  • the product containing sodium chloride fractions (product located by UV) are cooled in an ice bath then loaded onto a column of Amberchrom CG-161 resin (5 mL).
  • the column is eluted with ice-cold water (40 mL) followed by ambient temperature 20% aqueous isopropanol (8 x 2.5 mL fractions).
  • the product containing, aqueous isopropanol fractions are diluted with an equal volume of water and concentrated under vacuum to approximately 5 mL volume. This solution is lyophilized to afford the title compound.
  • Step 1 Allyl (3-[1(R)-( tert -butyl-dimethyl-silanyloxy)-ethyl]-2- ⁇ 3-[4-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultamyl]-1(R)-methyl-2-oxo-pentyl ⁇ -4-oxo-(3S,4S)-azetidin-1-yl)-(triphenyl-phosphoranylidene)-acetate
  • the solution is transferred via Teflon tubing to a precooled (-78°C) solution of allyl ⁇ 3-[1(R)-( tert -butyl-dimethyl-silanyloxy)-ethyl]-2-oxo-4-[1(R)-(pyridin-2-ylthiocarbonyl)-ethyl]-(3S,4S)-azetidin-1-yl ⁇ -(triphenylphosphoranylidine)-acetate (1.51 g, 2 mmol) in anhydrous tetrahydrofuran (10 mL).
  • the resulting solution is stirred under a nitrogen atmosphere at -78°C for 30 minutes, then allowed to gradually warm to 0°C over a period of 60 minutes.
  • the reaction mixture is diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts are washed with water (100 mL) and brine (100 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum.
  • the crude product is purified by chronatography on silica gel to afford the title compound.
  • Step 2 Allyl (1S,5R,6S)-6-[1(R)-( tert -butyl-dimethyl-silanyloxy)-ethyl]-1-methyl-2- ⁇ 1-[4-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultamyl]-propyl ⁇ -carbapen-2-em-3-carboxylate
  • the diastereomeric mixture is separated by silica gel column chromatograpy or by preparative HPLC.
  • the individual diastereomers, isomeric at the 2'-position, are processed according to steps 3-5 to give diastereomerically pure final products.
  • the crude alcohol (ca. 0.39 mmol) is dissolved in anhydrous dichloromethane (7.8 mL) and the solution is cooled in an ice-methanol bath (-20°C) and stirred under a nitrogen atmosphere.
  • 2,6-Lutidine (0.135 mL, 1.16 mmol) and trifluoro-methanesulfonic anhydride (0.098 mL, 0.58 mmol) are added sequentially.
  • the reaction mixture is stirred at -20°C to -15°C for 40 minutes, then diluted with dichloromethane (25 mL) and washed with water (20 mL), 0.1N hydrochloric acid (20 mL) and 50% brine (20 mL).
  • the organic layer is dried over magnesium sulfate, filtered, and evaporated under vacuum to provide the title compound.
  • the crude product is dissolved in 1:1 acetonitrile-water (1 mL) and the solution loaded onto a column of Bio-Rad Macro Prep CM ion exchange resin (3 mL).
  • the column is eluted with 1:1 acetonitrile-water (4 mL), water (3 x 5 mL), and 5% aqueous sodium chloride (10 x 2 mL).
  • the product containing NaCl fractions are cooled in ice then loaded onto a column of Amberchrom CG-161 resin (3 mL).
  • the column is eluted with ice-cold water (3 x 5 mL) followed by ambient temperature 20% aqueous isopropanol (5 x 3 mL).
  • the product containing 20% iPrOH fractions are combined, diluted with water (5 mL), concentrated under vacuum to ca. 4 mL volume, and lyophilized to afford the title compound.

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Claims (19)

  1. Composé représenté par la formule I :
    Figure 00850001
    incluant des sels pharmaceutiquement acceptables de celui-ci, où :
    R1 représente H ou un groupe méthyle ;
    CO2M représente un acide carboxylique, un anion carboxylate, un groupe ester pharmaceutiquement acceptable ou un acide carboxylique protégé par un groupe protecteur ;
    P représente un atome d'hydrogène, un groupe hydroxyle, F ou hydroxyle protégé par un groupe protecteur de groupe hydroxyle ;
    R2 représente H et R3 représente un groupe alkyle en C1-3, ou R2 et R3 pris en combinaison représentent un groupe alkylidène en C1-3 ;
    L représente un groupe alkylène en C1-4 linéaire ou ramifié, ininterrompu ou interrompu ou terminé par 1-2 parmi O, S, NRa, C(O), CO2 et C(O)NRa ;
    Q représente :
    Figure 00850002
    Y- représente un groupe d'équilibrage des charges ;
    Ra représente H ou un groupe alkyle en C1-6 ;
    Rq représente un groupe alkyle en C1-6, linéaire ou ramifié, ininterrompu ou interrompu ou terminé par 1-2 parmi O, S, NRa, C(O), C(O)O, C(O)NRa, -CH=CH-, -Het (Rb)3- , -C(O)Het (Rb)3-, -C(O)NraHet(Rb)3-
    Figure 00860001
       et
    ledit Rq étant non substitué ou substitué par 1-3 groupes Rc ;
    Het représente un groupe hétéroaryle ;
    chaque Rb est indépendamment choisi parmi H, un atome d'halogène, ORa, OC(O)Ra, C(O)Ra, CN, C(O)NCRaRd, NO2, NRaRd, SO2NRaRd et un groupe alkyle en C1-4 non substitué ou substitué par 1-3 groupes choisis parmi Re ;
    chaque Rc est indépendamment choisi parmi un atome d'halogène, un groupe alkyle en C1-4, ORf, OC(O)Rf, SRf, S(O)Rf, SO2Rf, CN, C(O)Rf, CO2Rf, NRfRg, C(O)NRaRf, -Het(Rb)3, C(=N+RaRf)Ra, C(=N+RaRf)NRaRf, NRaC(=N+RaRf)Ra, NRaC(=N+RaRf)NRaRf, heteroarylium(Rb)3, SO2NRaRf, OC(O)NRaRf, NRaC(O)Rf, NRaC(O)NRaRf, et
    Figure 00860002
       ou, comme alternative, lorsque 2 groupes Rc ou plus sont présents, 2 groupes Rc peuvent être pris ensemble avec des atomes intermédiaires quelconques pour former un cycle carboxylique à 3-6 chaínons, et éventuellement interrompu par 1-2 parmi O, S, NRg et C(O), ledit cycle étant non substitué ou substitué par 1-3 groupes Re ;
    Rd représente H ou un groupe alkyle en C1-4, ou Ra et Rd pris ensemble avec des atomes intermédiaires quelconques représentent un cycle à 4-6 chaínons ;
    chaque Re est indépendamment choisi parmi un atome d'halogène, ORa, RaRd et CONRaRd ;
    Rf représente H ; un groupe alkyle en C1-6 à chaíne linéaire ou ramifiée, non substitué ou substitué par 1-3 groupes Re ; -Het(Rb)3 ; un groupe cycloalkyle en C3-6, non substitué ou substitué par 1-3 groupes Re, et
    Figure 00870001
       ou Ra et Rf ensemble avec des atomes intermédiaires forment un cycle à 4-6 chaínons, éventuellement interrompus par O, S, NRa ou C(O) ;
    Rg représente H, un groupe alkyle en C1-6, non substitué ou substitué par 1-3 groupes Re ; un groupe cycloalkyle en C3-6, non substitué par 1-3 groupes Re ; C(=NRaRf)Ra, ou C(=NRaRf)NRaRf,
       ou Rf et Rg ensemble avec des atomes intermédiaires quelconques forment un cycle à 4-6 chaínons éventuellement interrompus par O, S, NRa ou C(O) ;
    Figure 00870002
    et chaque R représente indépendamment Rb, -Het(Rb)3 ou un groupe alcényle en C2-6,
       ou un groupe R peut être pris avec L et des atomes intermédiaires quelconques pour représenter un cycle à 5-6 chaínons.
  2. Composé selon la revendication 1, dans lequel R1 représente un groupe méthyle.
  3. Composé selon la revendication 1 dans lequel CO2M représente un anion carboxylate.
  4. Composé selon la revendication 1, dans lequel P représente un groupe hydroxyle ou un groupe hydroxyle protégé par un groupe protecteur de groupe hydroxyle.
  5. Composé selon la revendication 1, dans lequel R2 représente H et R3 représente un groupe alkyle en C1-3.
  6. Composé selon la revendication 5, dans lequel R2 représente H et R3 représente CH3 ou CH2CH3.
  7. Composé selon la revendication 1, dans lequel R2 et R3 sont pris en combinaison et représentent un groupe alkylidène en C1-3.
  8. Composé selon la revendication 7, dans laquelle R2 et R3 sont pris en combinaison pour représenter =CH2 ou =CHMe.
  9. Composé selon la revendication 1, dans lequel R représente -CH2 ou -CH2CH2-.
  10. Composé selon la revendication 1 dans lequel Q représente
    Figure 00880001
    où Y- représente un groupe d'équilibrage des charges.
  11. Composé selon la revendication 1, dans lequel Rq représente un groupe alkyle en C1-6 linéaire ou ramifié, éventuellement interrompu par -C(O)NRa-
    Figure 00880002
    et substitué par 1-3 groupes Rc.
  12. Composé selon la revendication 1, représenté par la formule I :
    Figure 00880003
    ou l'un de ses sels pharmaceutiquement acceptables, où :
    R1 représente CH3 ;
    CO2M représente un anion carboxylate ;
    P représente un groupe hydroxyle ou hydroxyle protégé par un groupe protecteur de groupe hydroxyle ;
    chaque R représente indépendamment H, un atome d'halogène ou un groupe alkyle en C1-4 non substitué ou substitué par 1-3 groupes choisis parmi les Re ;
    Ra représente H ou un groupe alkyle en C1-6 ;
    Rd représente H ou un groupe alkyle en C1-4 ou Ra et Rd pris ensemble avec des atomes intermédiaires quelconques représentent un cycle à 4-6 chaínons ;
    chaque Re est indépendamment choisi parmi un atome d'halogène, ORa, NRaRd et CONRaRd ;
    R2 représente H et R3 représente un groupe alkyle en C1-3 ;
    L représente -CH2- ou -CH2CH2- ;
    Q représente
    Figure 00890001
    où Y- représente un groupe d'équilibrage des charges et Rq représente un groupe alkyle en C1-6 linéaire ou ramifié, éventuellement interrompu par -C(O)NRa o
    Figure 00890002
    et substitué par 1-3 groupes Rc et
    Rc est tel qu'originellement défini.
  13. Composé selon la revendication 12, dans lequel R2 représente H et R3 représente CH3 ou CH2CH3.
  14. Composé selon la revendication 1 représenté par la formule I
    Figure 00900001
    ou l'un de ses sels pharmaceutiquement acceptables, où :
    R1 représente un groupe méthyle ;
    CO2M représente un anion carboxylate ;
    P représente un groupe hydroxyle ou hydroxyle protégé par un groupe protecteur de groupe hydroxyle ;
    chaque R représente indépendamment H, un atome d'halogène ou un groupe alkyle en C1-4 non substitué ou substitué par 1-3 groupes choisis parmi les Re ;
    Ra représente H ou un groupe alkyle en C1-6 ;
    Rd représente H ou un groupe alkyle en C1-4 ou Ra et Rd pris ensemble avec des atomes intermédiaires quelconques représentent un cycle à 4-6 chaínons ;
    Re représente un atome d'halogène, ORa, NRaRd et CONRaRd ;
    R2 et R3 sont pris en combinaison et représentent un groupe alkylidène en C1-3 ;
    L représente -CH2- ou -CH2CH2- ;
    Q représente
    Figure 00900002
    où Y- représente un groupe d'équilibrage des charges et
    Rq représente un groupe alkyle en C1-6 linéaire ou ramifié, éventuellement interrompu par -C(O)NRa o
    Figure 00900003
    et substitué par 1-3 groupes Rc.
  15. Composé selon la revendication 14, dans lequel R2 et R3 sont pris en combinaison pour représenter =CH2 ou =CHMe.
  16. Composé selon la revendication 1 ayant une structure conforme à ce qui suit :
    Figure 00910001
    Figure 00920001
    Figure 00930001
    Figure 00940001
    Figure 00950001
    Figure 00960001
    où X- représente un contre-ion.
  17. Composé selon la revendication 1 ayant une formule structurale conforme à l'une des suivantes
    Figure 00960002
    Figure 00970001
    Figure 00980001
    Figure 00990001
    Figure 01000001
    Figure 01010001
    Figure 01020001
    Figure 01030001
    Figure 01040001
    où X- représente un contre-ion.
  18. Composition pharmaceutique constituée d'un composé selon la revendication 1 en combinaison avec un véhicule pharmaceutiquement acceptable.
  19. Composé selon la revendication 1, destiné à être utilisé dans une méthode de traitement d'une infection bactérienne comprenant l'administration à un patient mammifère nécessitant un tel traitement d'un dit composé tel que défini dans la revendication 1 en une quantité qui est efficace pour le traitement d'une infection bactérienne.
EP98953450A 1997-10-15 1998-10-13 Carbapenemes antibacteriens, compositions et methodes de traitement Expired - Lifetime EP1023062B1 (fr)

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GBGB9806684.8A GB9806684D0 (en) 1998-03-27 1998-03-27 Carbapenem antibacterial compounds, compositions containing such compounds and ethods of treatment
PCT/US1998/021593 WO1999018954A1 (fr) 1997-10-15 1998-10-13 Carbapenemes antibacteriens, compositions et methodes de traitement

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